The overarching goal of this proposal is to demonstrate obesity-induced neuroinflammation in the raphe nucleus decreases serotonin synthesis which decreases hippocampal serotonin levels, thereby providing a neurochemical mechanism for co-morbid depressive illness in obesity. The incidence of obesity is greater in the VA population when compared with the general adult US population, with current estimates suggesting that over 80% of Veterans may be classified as obese or overweight. The complications of obesity extend to the central nervous system (CNS) and include an increased risk of developing neuropsychiatric co-morbidities like depressive illness. Unfortunately, these epidemiological studies cannot determine the neurochemical mechanism for this comorbidity. Clinical studies provide some insight into this unanswered question in that obese individuals are more likely to exhibit treatment resistance to serotonin selective uptake inhibitors (SSRIs) when compared to non- obese individuals. Obesity is characterized by chronic mild inflammation and neuroinflammation has been proposed to be responsible for decreases in serotonergic activity in co-morbid obesity and depression. In spite of these advances, several critical questions remain to be addressed: 1) is neuroinflammation increased in the raphe nucleus in obesity?; 2) does raphe nucleus neuroinflammation decrease serotonin (5-HT) synthesis in the raphe nucleus and thereby decrease hippocampal 5-HT levels? and 3) can we identify treatment strategies to reverse these changes and/or readily accessible biomarkers that drive this comorbidity? Decreases in brain 5-HT levels are proposed to be a critical factor in the pathogenesis of depressive illness. Interestingly, our ongoing studies suggest that hippocampal 5-HT levels are significantly reduced in obese rats, thereby providing a potential neurochemical mechanism through which obesity increases the risk of neuropsychiatric disorders. As the raphe nucleus is the primary site of synthesis of 5-HT in the brain, neuroinflammation in the raphe nucleus may be a critical site for the neurochemical deficits that drive depressive illness in obesity. In view of these observations, the hypothesis of this proposal is that leptin resistance in the raphe nucleus decreases hippocampal 5-HT efflux, thereby providing a neurochemical mechanism for comorbid depressive illness in obesity. This hypothesis will be tested in the following Aims. ? Aim 1 will determine whether neuroinflammation in the raphe nucleus decreases 5-HT synthesis and SSRI responses in the hippocampus of obese male and female rodents. ? Aim 2 will determine whether lifestyle interventions that are consistent with the VA MOVE! weight management program can reverse obesity-induced neuroinflammation, 5-HT deficits and depressive- like behaviors in obese rats. Collectively, these studies will identify raphe nucleus neuroinflammation as the locus and neurochemical mechanism for comorbid depressive illness in obese individuals. Most importantly, our studies will provide further evidence for the importance of the MOVE! Program, particularly as it relates to the improvement of neuropsychiatric health of obese Veterans.